Autoimmune diseases arise on account of a reactivity of the immune system to the body's own structures. In this connection the tolerance that normally exists with respect to the body's own tissues is destroyed. Apart from antibodies, in particular T lymphocytes and monocytes/macrophages play a decisive role in the pathogenesis of the various autoimmune diseases. Activated monocytes/macrophages secrete a large number of different inflammation-promoting mediators that are directly or indirectly responsible for the destruction of the tissues affected by the autoimmune disease. The activation of monocytes/macrophages takes place either in the interaction with T lymphocytes or via bacterial products such as lipopolysaccharide (LPS). An inflammation-promoting substance formed by activated monocytes/macrophages is interleukin-12 (IL-12).
IL-12 is a heterodimeric molecule that consists of a covalently bound p35 and p40 chain. It is formed by antigen-presenting cells (monocytes/macrophages, dentritic cells, B lymphocytes) after activation by various microbial products such as LPS, lipopeptides, bacterial DNA or in the interaction with activated T lymphocytes (Trinchieri 1995, Ann. Rev. Immunol. 13: 251). IL-12 has a central immunoregulatory importance and is responsible for the development of inflammation-promoting TH1 reactions. The existence of a TH1 immune reaction to the body's own antigens leads to serious diseases, as is clearly documented in numerous animal experiment and initial clinical investigations. The pathophysiological importance of IL-12 (Trembleau et al. 1995, Immunol. Today 16: 383; Müller et al. 1995 J. Immunol. 155: 4661 Neurath et al. 1995, J. Exp. Med. 182: 1281; Segal et al. 1998. J. Exp. Med. 187: 537; Powrie et al. 1995. Immunity 3: 171; Rudolphi et al. 1996, Eur. J. Immunol. 26: 1156; Bregenholt et al. 1998, Eur. J. Immunol. 28: 379) is manifested in various animal models for diseases such as rheumatoid arthritis, multiple sclerosis, diabetes mellitus as well as inflammatory intestinal, skin and mucous membrane diseases. The respective disease could be triggered by application of IL-12; after neutralisation of endogenous IL-12 there was a remission of the disease symptoms, and eventually a healing of the animals. The use of antibodies against IL-12 in humans is currently being investigated.
The cytokine IL-10 inhibits the synthesis of the inflammation-promoting cytokines TNFα, IL-1, IL-6, IL-8, IL-12 and GM-CSF by human and murine monocytes/macrophages (Fiorentino et al., 1991, J. Immunol. 146: 3444; De Waal Malefyt et al. 1991. J. Exp. Med. 174: 1209). This inhibition also leads indirectly to a blocking of the synthesis of IFN-γ by TH1 lymphocytes. Interestingly, the formation of IL-10 by monocytes/macrophages occurs with a slight time delay compared to the synthesis of the inflammation-promoting cytokines. The treatment of antigen-presenting cells with IL-10 results in their deactivation. Such cells are not able to activate T lymphocytes for the proliferation or the synthesis of IFN-γ. However, these T lymphocytes themselves secrete large amounts of IL-10 and are able to suppress inflammation reactions, as has been shown by the example of an animal model of inflammatory intestinal diseases (Groux et al., 1997. Nature 389: 737). Also, the development of inflammatory skin diseases can be prevented by IL-10 (Enk et al., 1994. J. Exp. Med, 179: 1397).
To summarize, it can be said that an excess of IL-12 or a lack of IL-10 is responsible for the pathophysiology of a large number of inflammatory/autoimmune diseases. Attempts to restore the equilibrium between inflammation-promoting (IL-12) and inflammation-inhibiting (IL-10) cytokines therefore have a large therapeutic potential as regards the diseases mentioned above.
IL-12 is furthermore also involved in the regulation of cell survival. Uncontrolled cell growth is regulated inter alia by apoptosis (programmed cell death). It was shown in T lymphocytes that IL-12 has an anti-apoptotic action and promotes the survival of T cells (Clerici et al. 1994, Proc. Natl. Acad. Sci. USA 91: 11811; Estaquier et al. 1995, J. Exp. Med. 182: 1759). A localized over-production of IL-12 may therefore contribute to the survival of tumor cells. Inhibitors of the formation of IL-12 accordingly also have a large therapeutic potential in the treatment of tumors.
A substance having the immunomodulating effect of inhibiting IL-12 and increasing IL-10 is thalidomide. Recent clinical studies have shown the positive influence of thalidomide on the following diseases: erythema nodosum leprosum (Sampaio et al. 1993, J. Infect. Dis. 168: 408), aphthosis (Jacobson et al. 1997, N. Engl. J. Med. 336: 1487), chronic rejection reactions (Vogelsang, et al. 1992, N. Engl. J. Med. 326: 1055), inflammatory intestinal diseases (Ehrenpreis et al. 1999, Gastroenterology 117: 1271); Vasitiauskas et al. 1999, Gastroenterology 117: 1278) as well as numerous skin diseases {Bernal et al. 1992, Int. J. Derm. 31; 599). Clinical studies are also in progress on the treatment of a number of tumor diseases (Rajkumar, 2001, Oncology 15: 867). An effect on multiple myeloma appears certain (Singhal, 1999, N. Engl. J. Med. 341: 1565). However, thalidomide also gives rise to a number of side effects, including sedation, teratogenicity and neuropathy. In addition the substance is sparingly soluble and highly sensitive to hydrolysis.